The major goal of this Program Project is to understand the immunopathology of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the severe complications of dengue virus infections. Dengue is an emerging flavivirus, like West Nile Virus, and is the most common serious arbovirus infection. The morbidity and mortality associated with severe dengue infections is a major public health problem that is increasing in frequency. The frequency of DHF/DSS is much greater during secondary infections with dengue virus strains of a different dengue serotype than that which caused the primary infection. These observations have slowed down vaccine development because of safety concerns. Project #1 consists of three clinical and epidemiology investigations in Thailand. One study is designed to define early immunopathological events during acute dengue infections and will focus on research questions raised during the first years of study. A prospective population-based study of school children is designed to define the roles of dengue cross-reactive T and B cell memory following primary infection on the clinical course of secondary dengue infection, and a study of dengue rashes is planned as a model of dengue pathogenesis. These clinical studies will provide data essential for the later testing of the safety and efficacy of dengue vaccines. Project #2 consists of research to define the host, viral and immunological factors, which induce capillary leakage in DHF .The roles of pre-existing cross-reactive, dengue specific T and B cell memory and of HLA alleles will be analyzed as host and immunological factors. Viral burden, virus-antibody complexes, and NK and T cell responses and immune activation will be assessed during acute infections to define the events leading to DHF. Project #3 will provide analyses of dengue cluster outbreaks as part of the school-based prospective study and determine the effects of vector control on these outbreaks. A Clinical Research Core and an Administrative Core are needed to support these research projects. Our ultimate goal is to develop an improved understanding of the immunopathology of DHF/DSS as a basis for the earlier diagnosis of children at highest risk, and as a foundation for developing logical and safe vaccine approaches to prevent this severe illness.